Abstract Systemic administration of a high-dose of Methylprednisolone (MP) can reduce neurological deficits after acute spinal cord injury (SCI). However, the use of high-dose MP in treating acute SCI is controversial due to significant dose related side effects and relatively modest improvements in neurological function. Here, using a rat model of SCI, we compare the efficacy of controlled, nanoparticle-enabled local delivery of MP to the injured spinal cord with systemic delivery of MP, and a single local injection of MP without nanoparticles. Based on histological and behavioral data, we report that local, sustained delivery of MP via nanoparticles is significantly more effective than systemic delivery. Relative to systemic delivery, MP-nanoparticle therapy significantly reduced lesion volume and improved behavioral outcomes. Nanoparticle-enabled delivery of MP presents an effective method for introducing MP locally after SCI and significantly enhances therapeutic effectiveness compared to bare MP administered either systemically or locally.